tbuckley/cabot-search huggingface dataset:
Genome-wide analyses characterize shared heritability among cancers and identify novel cancer susceptibility regions
Authors: Sara Lindström, Lu Wang, Helian Feng, Arunabha Majumdar, Sijia Huo, James Macdonald, Tabitha Harrison, Constance Turman, Hongjie Chen, Nicholas Mancuso, Theo Bammler, Steve Gallinger, Stephen B Gruber, Marc J Gunter, Loic Le Marchand, Victor Moreno, Kenneth Offit, Immaculata De Vivo, Tracy A O’Mara, Amanda B Spurdle, Ian Tomlinson, Rebecca Fitzgerald, Puya Gharahkhani, Ines Gockel, Janusz Jankowski, Stuart Macgregor, Johannes Schumacher, Jill Barnholtz-Sloan, Melissa L Bondy, Richard S Houlston, Robert B Jenkins, Beatrice Melin, Margaret Wrensch, Paul Brennan, David C Christiani, Mattias Johansson, James Mckay, Melinda C Aldrich, Christopher I Amos, Maria Teresa Landi, Adonina Tardon, D Timothy Bishop, Florence Demenais, Alisa M Goldstein, Mark M Iles, Peter A Kanetsky, Matthew H Law, Laufey T Amundadottir, Rachael Stolzenberg-Solomon, Brian M Wolpin, Alison Klein, Gloria Petersen, Harvey Risch, Stephen J Chanock, Mark P Purdue, Ghislaine Scelo, Paul Pharoah, Siddhartha Kar, Rayjean J Hung, Bogdan Pasaniuc, Peter Kraft
Journal: JNCI Journal of the National Cancer Institute (2023)

Abstract Background The shared inherited genetic contribution to risk of different cancers is not fully known. In this study, we leverage results from 12 cancer genome-wide association studies (GWAS) to quantify pairwise genome-wide genetic correlations across cancers and identify novel cancer susceptibility loci. Methods We collected GWAS summary statistics for 12 solid cancers based on 376 759 participants with cancer and 532 864 participants without cancer of European ancestry. The included cancer types were breast, colorectal, endometrial, esophageal, glioma, head and neck, lung, melanoma, ovarian, pancreatic, prostate, and renal cancers. We conducted cross-cancer GWAS and transcriptome-wide association studies to discover novel cancer susceptibility loci. Finally, we assessed the extent of variant-specific pleiotropy among cancers at known and newly identified cancer susceptibility loci. Results We observed widespread but modest genome-wide genetic correlations across cancers. In cross-cancer GWAS and transcriptome-wide association studies, we identified 15 novel cancer susceptibility loci. Additionally, we identified multiple variants at 77 distinct loci with strong evidence of being associated with at least 2 cancer types by testing for pleiotropy at known cancer susceptibility loci. Conclusions Overall, these results suggest that some genetic risk variants are shared among cancers, though much of cancer heritability is cancer-specific and thus tissue-specific. The increase in statistical power associated with larger sample sizes in cross-disease analysis allows for the identification of novel susceptibility regions. Future studies incorporating data on multiple cancer types are likely to identify additional regions associated with the risk of multiple cancer types.
Neutropenia in patients on dupilumab for atopic dermatitis: a case series and review of trial data
Authors: Pirunthan Pathmarajah, Roberto Corso, Amr  Salam, Gulnaz Shah, Richard Woolf, Catherine H Smith, Andrew E Pink
Journal: British Journal of Dermatology (2023)

Journal Article Neutropenia in patients on dupilumab for atopic dermatitis: a case series and review of trial data Get access Pirunthan Pathmarajah, Pirunthan Pathmarajah St John’s Institute of Dermatology Correspondence: Pirunthan Pathmarajah. Email: pirunthan.pathmarajah@nhs.net Search for other works by this author on: Oxford Academic Google Scholar Roberto Corso, Roberto Corso St John’s Institute of Dermatology Search for other works by this author on: Oxford Academic Google Scholar Amr Salam, Amr Salam St John’s Institute of Dermatology Search for other works by this author on: Oxford Academic Google Scholar Gulnaz Shah, Gulnaz Shah Department of Haematology, Guy’s and St Thomas’ NHS Foundation Trust, London, UK Search for other works by this author on: Oxford Academic Google Scholar Richard Woolf, Richard Woolf St John’s Institute of Dermatology Search for other works by this author on: Oxford Academic Google Scholar Catherine H Smith, Catherine H Smith St John’s Institute of Dermatology Search for other works by this author on: Oxford Academic Google Scholar Andrew E Pink Andrew E Pink St John’s Institute of Dermatology Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 188, Issue 6, June 2023, Pages 803–805, https://doi.org/10.1093/bjd/ljad038 Published: 17 March 2023 Article history Received: 21 July 2022 Revision received: 08 February 2023 Published: 17 March 2023 Corrected and typeset: 28 March 2023
Spatial variation of the gut microbiome in response to long-term metformin treatment in high-fat diet-induced type 2 diabetes mouse model of both sexes
Authors: Laila Silamiķele, Rihards Saksis, Ivars Silamiķelis, Patrīcija Paulīne Kotoviča, Monta Brīvība, Ineta Kalniņa, Zane Kalniņa, Dāvids Fridmanis, Jānis Kloviņš
Journal: Gut Microbes (2023)

Antidiabetic drug metformin alters the gut microbiome composition in the context of type 2 diabetes and other diseases; however, its effects have been mainly studied using fecal samples, which offer limited information about the intestinal site-specific effects of this drug. Our study aimed to characterize the spatial variation of the gut microbiome in response to metformin treatment by using a high-fat diet-induced type 2 diabetes mouse model of both sexes. Four intestinal parts, each at the luminal and mucosal layer level, were analyzed in this study by performing 16S rRNA sequencing covering six variable regions (V1-V6) of the gene and thus allowing to obtain in-depth information about the microbiome composition. We identified significant differences in gut microbiome diversity in each of the intestinal parts regarding the alpha and beta diversities. Metformin treatment altered the abundance of different genera in all studied intestinal sites, with the most pronounced effect in the small intestine, where Lactococcus increased remarkably. The abundance of Lactobacillus was substantially lower in male mice compared to female mice in all locations, in addition to an enrichment of opportunistic pathogens. Diet type and intestinal layer had significant effects on microbiome composition at each of the sites studied. We observed a different effect of metformin treatment on the analyzed subsets, indicating the multiple dimensions of metformin's effect on the gut microbiome.
Vision rescue via unconstrained in vivo prime editing in degenerating neural retinas
Authors: Huan Qin, Wenliang Zhang, Shiyao Zhang, Yuan Feng, Weihui Xu, Jia Qi, Qian Zhang, Chunxiu Xu, Shanshan Liu, Jia Zhang, Yushuang Lei, Wanqin Liu, Shuyu Feng, Jingjing Wang, Xuefei Fu, Zifen Xu, Ping Li, Kai Yao
Journal: The Journal of Experimental Medicine (2023)

Retinitis pigmentosa (RP) is an inherited retinal dystrophy causing progressive and irreversible loss of retinal photoreceptors. Here, we developed a genome-editing tool characterized by the versatility of prime editors (PEs) and unconstrained PAM requirement of a SpCas9 variant (SpRY), referred to as PESpRY. The diseased retinas of Pde6b-associated RP mouse model were transduced via a dual AAV system packaging PESpRY for the in vivo genome editing through a non-NGG PAM (GTG). The progressing cell loss was reversed once the mutation was corrected, leading to substantial rescue of photoreceptors and production of functional PDE6β. The treated mice exhibited significant responses in electroretinogram and displayed good performance in both passive and active avoidance tests. Moreover, they presented an apparent improvement in visual stimuli-driven optomotor responses and efficiently completed visually guided water-maze tasks. Together, our study provides convincing evidence for the prevention of vision loss caused by RP-associated gene mutations via unconstrained in vivo prime editing in the degenerating retinas.
In‐Depth Occlusion of Dentinal Tubules and Rapid Remineralization of Demineralized Dentin Induced by Polyelectrolyte‐Calcium Complexes
Authors: Zihuai Zhou, Jiachen Li, Zhe Wang, Hongli Zhang, Yiru Wang, Dongni Shen, Zhifang Wu, Minjuan Shen, Haihua Pan, Qi Wang, Ruikang Tang, Matthias Hannig, Baiping Fu
Journal: Advanced Healthcare Materials (2023)

Abstract Dentin hypersensitivity (DH) is triggered by external stimuli irking fluid flow through exposed dentinal tubules (DTs). Three commercially available desensitizing agents as control in this study only achieve limited occlusion depths of ≈10 µm in the DTs as well as scarce remineralization of demineralized dentin matrix. Herein, polyelectrolyte‐calcium complexes pre‐precursor (PCCP) process is proposed for managing DH that demineralized dentin with exposed DTs is rubbed with ultrahighly concentrated polyelectrolyte‐calcium suspension (4 g L −1 ‐5.44 m ) followed by phosphate solution (3.25 m ), each 10 min, leading to heavy remineralization of demineralized dentin and compact occlusion of the DTs over 200 µm after 1 day of in vitro and in vivo incubation. For the first time, it is demonstrated that the PCCP process relies on the pH‐dependent electrostatic attraction between electropositive polyelectrolyte‐calcium complexes and electronegative inwalls of DTs comprised of collagen fibrils and hydroxyapatite crystals under alkaline condition. The PCCP process might shed light on a promising dentin desensitizing strategy for DH management via rapid in‐depth DT occlusion and remineralization of demineralized dentin.
The host-targeting compound peruvoside has a broad-spectrum antiviral activity against positive-sense RNA viruses
Authors: Kan Xing Wu, Thinesshwary Yogarajah, Marcus Wing Choy Loe, Parveen Kaur, Regina Ching Hua Lee, Chee Keng Mok, Yi Hao Wong, Patchara Phuektes, Li Sze Yeo, Vincent T.K. Chow, Yong Wah Tan, Justin Jang Hann Chu
Journal: Acta Pharmaceutica Sinica B (2023)

Positive-sense RNA viruses modify intracellular calcium stores, endoplasmic reticulum and Golgi apparatus (Golgi) to generate membranous replication organelles known as viral factories. Viral factories provide a conducive and substantial enclave for essential virus replication via concentrating necessary cellular factors and viral proteins in proximity. Here, we identified the vital role of a broad-spectrum antiviral, peruvoside in limiting the formation of viral factories. Mechanistically, we revealed the pleiotropic cellular effect of Src and PLC kinase signaling via cyclin-dependent kinase 1 signaling leads to Golgi-specific brefeldin A-resistance guanine nucleotide exchange factor 1 (GBF1) phosphorylation and Golgi vesiculation by peruvoside treatment. The ramification of GBF1 phosphorylation fosters GBF1 deprivation consequentially activating downstream antiviral signaling by dampening viral factories formation. Further investigation showed signaling of ERK1/2 pathway via cyclin-dependent kinase 1 activation leading to GBF1 phosphorylation at Threonine 1337 (T1337). We also showed 100% of protection in peruvoside-treated mouse model with a significant reduction in viral titre and without measurable cytotoxicity in serum. These findings highlight the importance of dissecting the broad-spectrum antiviral therapeutics mechanism and pave the way for consideration of peruvoside, host-directed antivirals for positive-sense RNA virus-mediated disease, in the interim where no vaccine is available.
SARS-CoV-2 variant-related abnormalities detected by prenatal MRI: direct or indirect effects of the infection must be demonstrated—Authors’ reply
Authors: Patric Kienast, Daniela Prayer, Julia Binder, Florian Prayer, Sabine Dekan, Eva Langthaler, Sabine Eichinger, Marlene Stuempflen, Christian Mitter, Gregor Kasprian
Journal: The Lancet Regional Health - Europe (2023)
Second Version of the Prostate Cancer Molecular Imaging Standardized Evaluation Framework Including Response Evaluation for Clinical Trials (PROMISE V2)
Authors: Robert Seifert, Louise Emmett, Steven P. Rowe, Ken Herrmann, Boris Hadaschik, Jeremie Calais, Frederik L. Giesel, Robert Reiter, Tobias Maurer, Matthias Heck, Andrei Gafita, Michael J. Morris, Stefano Fanti, Wolfgang A. Weber, Thomas A. Hope, Michael S. Hofman, Wolfgang Peter Fendler, Matthias Eiber
Journal: European Urology (2023)

Prostate-specific membrane antigen (PSMA) targeting positron emission tomography (PET) is emerging to become a reference imaging tool for the staging and restaging of patients with prostate cancer for both clinical routine and trials. The prostate cancer molecular imaging standardized evaluation (PROMISE) criteria have been proposed as a framework for whole-body staging (molecular imaging TNM staging, denoted miTNM staging) to describe the prostate cancer disease extent on PSMA-PET.To create a comprehensive and integrated framework for PSMA-PET image interpretation and reporting.We propose the PROMISE V2 framework, which integrates an updated miTNM system, improved assessment of local disease, and a slightly modified PSMA-expression score for clinical routine. We have added a response monitoring framework defining qualitative and quantitative parameters to be recorded for a longitudinal assessment in clinical trials.We provide a comprehensive literature review on the current use of the PROMISE framework in clinical research and prospective trials. PROMISE variables demonstrate a clear association with survival. PSMA expression assessed by the PSMA-expression score was used in several trials, and a low PSMA-expression score is a negative prognosticator of overall survival after 177Lu-PSMA radioligand therapy. The proposed imaging parameters recorded for response assessment in clinical trials can be utilized to determine response according to PSMA-PET progression (PPP) or Response Evaluation Criteria in PSMA-PET/Computed Tomography (RECIP) frameworks, but also future response criteria.PROMISE V2 offers standardized reporting of disease extent for clinical routine and research. Parameters recorded within clinical trials facilitate objective response assessment.Prostate-specific membrane antigen (PSMA) targeting positron emission tomography (PET) has become a standard imaging examination for prostate cancer. We propose a comprehensive framework for the analysis and reporting of PSMA-PET findings that will improve the communication between imaging experts and uro-oncologists.
Double trouble during peroral endoscopic myotomy for achalasia cardia: myotomy to the rescue
Authors: Harshal S. Mandavdhare, Rajeev Chauhan, Harjeet Singh, Pankaj Gupta, Usha Dutta
Journal: Endoscopy (2023)

Peroral endoscopic myotomy (POEM) is now the established modality of choice for achalasia cardia with good long-term efficacy [1]. Dislodgement of the distal attachment (hood) inside the tunnel is an uncommon intraoperative event. The retrieval of a dislodged hood can be troublesome at or beyond the lower esophageal sphincter (LES). Here we share a case of POEM for achalasia cardia where the patient developed a dual problem of a type II mucosal injury and dislodgement of the hood at the level of the LES that was tackled with myotomy.
Early gastric mucosa-associated lymphoid tissue lymphoma treated by endoscopic submucosal dissection
Authors: Yu Wu, Yong Li, Xiaowei Liu
Journal: Endoscopy (2023)

A previously healthy 66-year-old woman was referred to our hospital for belching with a positive 13C-labeled urea breath test. A coarse nodular lesion was observed upon upper endoscopy ([Fig. 1 a]). She was treated with standard H. pylori quadruple therapy for 2 weeks.
Endoscopic resection of a gastric gastrointestinal stromal tumor without perforation using a detachable snare
Authors: Hironao Matsumoto, Takeshi Yamashina, Masaaki Shimatani, Masahiro Orino, Masataka Kano, Takafumi Yuba, Makoto Naganuma
Journal: Endoscopy (2023)

Resection of gastrointestinal stromal tumors (GISTs) by endoscopic submucosal dissection (ESD) has recently been reported [1] [2]. However, when endoscopic resection is performed, a full-layer resection of the gastric wall is often necessary, and extensive suturing is required if perforation occurs. We report the case of a patient with a GIST that was completely resected safely and easily without perforation using the ESD technique in combination with a detachable snare.
Gel immersion endoscopic papillectomy using a double-balloon endoscope to resect an ampullary tumor
Authors: Takeshi Kasai, Masaaki Shimatani, Toshiyuki Mitsuyama, Takeshi Yamashina, Masataka Kano, Takakuni Yuba, Makoto Naganuma
Journal: Endoscopy (2023)

The usefulness of underwater endoscopic papillectomy for treating ampullary tumors in patients with surgically altered anatomy has been reported [1], but difficulties in managing the water flow in the gastrointestinal tract, and the nature of water, which mixes with blood and bile, thus impairing the endoscopic view, remained to be overcome.
Universal Germline and Tumor Genomic Testing Needed to Win the War Against Cancer: <i>Genomics Is the Diagnosis</i>
Authors: Vivek Subbiah, Razelle Kurzrock
Journal: Journal of Clinical Oncology (2023)

Advances in the genomic era have led to identification of cancer-causing genes and unprecedented progress in the development of gene-targeted therapies and agents that can unleash the immune system.These advances have improved the outlook for patients with lethal malignancies.Cancer is a genomic disease in that gene alterations drive the cellular growth and immune surveillance perturbations that enable malignant cells to take hold and to metastasize.Hereditary genetic factors play a key role in cancer predisposition, initiation, prognosis, and therapy.In a previous viewpoint, we posited that we need universal (somatic) genomic testing to win the war against cancer. 1 Currently, given the rapidly emerging evidence, we update our view to state that universal germline, in addition to tumor somatic, genomic testing is needed to win the war against cancer.
Long-Term Performance of an Image-Based Short-Term Risk Model for Breast Cancer
Authors: Mikael Eriksson, Kamila Czene, Celine Vachon, Emily F. Conant, Per Hall
Journal: Journal of Clinical Oncology (2023)

Image-derived artificial intelligence-based short-term risk models for breast cancer have shown high discriminatory performance compared with traditional lifestyle/familial-based risk models. The long-term performance of image-derived risk models has not been investigated.We performed a case-cohort study of 8,604 randomly selected women within a mammography screening cohort initiated in 2010 in Sweden for women age 40-74 years. Mammograms, age, lifestyle, and familial risk factors were collected at study entry. In all, 2,028 incident breast cancers were identified through register matching in May 2022 (206 incident breast cancers were found in the subcohort). The image-based model extracted mammographic features (density, microcalcifications, masses, and left-right breast asymmetries of these features) and age from study entry mammograms. The Tyrer-Cuzick v8 risk model incorporates self-reported lifestyle and familial risk factors and mammographic density to estimate risk. Absolute risks were estimated, and age-adjusted AUC model performances (aAUCs) were compared across the 10-year period.The aAUCs of the image-based risk model ranged from 0.74 (95% CI, 0.70 to 0.78) to 0.65 (95% CI, 0.63 to 0.66) for breast cancers developed 1-10 years after study entry; the corresponding Tyrer-Cuzick aAUCs were 0.62 (95% CI, 0.56 to 0.67) to 0.60 (95% CI, 0.58 to 0.61). For symptomatic cancers, the aAUCs for the image-based model were ≥0.75 during the first 3 years. Women with high and low mammographic density showed similar aAUCs. Throughout the 10-year follow-up, 20% of all women with breast cancers were deemed high-risk at study entry by the image-based risk model compared with 7.1% using the lifestyle familial-based model (P < .01).The image-based risk model outperformed the Tyrer-Cuzick v8 model for both short-term and long-term risk assessment and could be used to identify women who may benefit from supplemental screening and risk reduction strategies.
A mast cell–thermoregulatory neuron circuit axis regulates hypothermia in anaphylaxis
Authors: Chunjing Bao, Ouyang Chen, Huaxin Sheng, Jeffrey Zhang, Yikai Luo, Byron W. Hayes, Han Liang, Wolfgang Liedtke, Ru-Rong Ji, Soman N. Abraham
Journal: Science Immunology (2023)

IgE-mediated anaphylaxis is an acute life-threatening systemic reaction to allergens, including certain foods and venoms. Anaphylaxis is triggered when blood-borne allergens activate IgE-bound perivascular mast cells (MCs) throughout the body, causing an extensive systemic release of MC mediators. Through precipitating vasodilatation and vascular leakage, these mediators are believed to trigger a sharp drop in blood pressure in humans and in core body temperature in animals. We report that the IgE/MC-mediated drop in body temperature in mice associated with anaphylaxis also requires the body’s thermoregulatory neural circuit. This circuit is activated when granule-borne chymase from MCs is deposited on proximal TRPV1 + sensory neurons and stimulates them via protease-activated receptor-1. This triggers the activation of the body’s thermoregulatory neural network, which rapidly attenuates brown adipose tissue thermogenesis to cause hypothermia. Mice deficient in either chymase or TRPV1 exhibited limited IgE-mediated anaphylaxis, and, in wild-type mice, anaphylaxis could be recapitulated simply by systemically activating TRPV1 + sensory neurons. Thus, in addition to their well-known effects on the vasculature, MC products, especially chymase, promote IgE-mediated anaphylaxis by activating the thermoregulatory neural circuit.
Development and Validation of a Diabetic Retinopathy Risk Stratification Algorithm
Authors: Dariusz Tarasewicz, Andrew J. Karter, Noel Pimentel, Howard H. Moffet, Khanh K. Thai, David Schlessinger, Oleg Sofrygin, Ronald B. Melles
Journal: Diabetes Care (2023)

OBJECTIVE Although diabetic retinopathy is a leading cause of blindness worldwide, diabetes-related blindness can be prevented through effective screening, detection, and treatment of disease. The study goal was to develop risk stratification algorithms for the onset of retinal complications of diabetes, including proliferative diabetic retinopathy, referable retinopathy, and macular edema. RESEARCH DESIGN AND METHODS Retrospective cohort analysis of patients from the Kaiser Permanente Northern California Diabetes Registry who had no evidence of diabetic retinopathy at a baseline diabetic retinopathy screening during 2008–2020 was performed. Machine learning and logistic regression prediction models for onset of proliferative diabetic retinopathy, diabetic macular edema, and referable retinopathy detected through routine screening were trained and internally validated. Model performance was assessed using area under the curve (AUC) metrics. RESULTS The study cohort (N = 276,794) was 51.9% male and 42.1% White. Mean (±SD) age at baseline was 60.0 (±13.1) years. A machine learning XGBoost algorithm was effective in identifying patients who developed proliferative diabetic retinopathy (AUC 0.86; 95% CI, 0.86–0.87), diabetic macular edema (AUC 0.76; 95% CI, 0.75–0.77), and referable retinopathy (AUC 0.78; 95% CI, 0.78–0.79). Similar results were found using a simpler nine-covariate logistic regression model: proliferative diabetic retinopathy (AUC 0.82; 95% CI, 0.80–0.83), diabetic macular edema (AUC 0.73; 95% CI, 0.72–0.74), and referable retinopathy (AUC 0.75; 95% CI, 0.75–0.76). CONCLUSIONS Relatively simple logistic regression models using nine readily available clinical variables can be used to rank order patients for onset of diabetic eye disease and thereby more efficiently prioritize and target screening for at risk patients.
Gut-microbiome-expressed 3β-hydroxysteroid dehydrogenase degrades estradiol and is linked to depression in premenopausal females
Authors: Di Li, Ting Sun, Yongqing Tong, Juan Le, Qian Yao, Jun Tao, Hang Liu, Woer Jiao, Yufeng Mei, Jingru Chen, Zhongchun Liu, Gaohua Wang, Yan Li
Journal: Cell Metabolism (2023)